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In thesis

Arabi, Azadeh

Södertörn University, School of Life Sciences. Karolinska Institutet.

2006 (English)Doctoral thesis, comprehensive summary (Other academic)

Abstract [en]

The transcription factor c-Myc is a key regulator of growth and proliferation. c-Myc levels are tightly controlled and deregulated c-Myc is often associated with human cancers. In our initial studies we observed that upon inhibition of proteasomes, excess c-Myc accumulates primarily in the nucleoli. After further investigation we could show that c-Myc binds to and activates RNA polymerase I-mediated transcription of the ribosomal RNA (rRNA) genes located in the nucleoli and that proteasomes are involved in this process. We demonstrate that upon an increase in c-Myc levels through either inhibition of the proteasomes or high expression, c-Myc accumulates in the nucleoli. The dynamics of the nucleoplasmic and the nucleolar c-Myc was studied in living cells expressing GFP-fused cMyc using the Fluorescent loss in photo-bleaching and the Fluorescent recovery after photobleaching techniques. We show that c-Myc is relatively stably associated with the nucleoli. In addition, we show that proteasomes accumulate and co-localise with nucleolar c-Myc. We further investigate the function of c-Myc in the nucleoli and show that c-Myc and Max interact in the nucleoli and are associated with the ribosomal DNA. Upon mitogenic stimulation of quiescent human lymphocytes c-Myc is recruited to the rRNA genes together with pol I. Association of c-Myc with the rDNA is also accompanied by an increase in rDNA histone acetylation and activation of rRNA transcription. Inhibition of c-Myc inhibits rRNA transcription. These results suggest that c-Myc plays a key role in regulating ribosome biogenesis and thus cell growth. We also show that proteasomes are required for activation of rRNA transcription, even though c-Myc levels increase in response to reduced proteasome activity. The role of proteasomes in rDNA transcription remains to be determined. We also investigate the role of c-Myc in regulation of the nucleolar organisation and induction of nucleolar alterations in cancer cells. Several types of human cancers with nucleolar alterations including cancers of blood, prostate and breast are also associated with deregulated levels of c-Myc. However, it is not known whether c-Myc contributes to the induction of nucleolar changes in these cancers. We show that despite high levels, c-Myc does not accumulate in the nucleoli in lymphoma and breast cancer cell lines. This is intriguing since nucleolar accumulation of excess c-Myc in other cell lines is associated with inhibition of rRNA transcription.